Summary Methods to preserve and store biomolecules and the tissues that contain them are essential to molecular characterization of disease and associated lesions. The long-used standard method for preserving such samples is formalin fixation. While this approach does preserve tissue morphology for microscopic examination, it creates extensive and complex adducts with the nucleic acids and proteins. For modern molecular analysis, these adducts interfere and must be removed. Unfortunately, harsh conditions are required, causing further damage and hindering recovery. Here we propose to develop an entirely new, fully reversible chemistry for biomolecule and tissue fixation that overcomes these problems. The approach is based on reversible acylation (REAC) chemistry, using specialized water-soluble, cell-permeable acylimidazole reagents to react with important functional groups of nucleic acids, proteins and carbohydrates. These adducts are expected to stabilize and crosslink the biomolecules indefinitely, and preserve tissue morphology. When molecular analysis is desired, the acyl groups can be removed virtually completely by addition of a second cell-permeable reagent (a soluble phosphine) under exceptionally mild conditions, restoring the molecular integrity of the biomolecules to their native states for analysis via amplification, sequencing, IHC or mass spectrometry. The hypotheses driving this research are (1) that REAC agents can provide general protection of biomolecules and tissue from biological degradation during fixation and storage; and (2) that the resulting adducts can be reversed in high yields to reveal native biomolecules with better integrity than formalin-fixation. The preliminary studies have shown that the prototype NAI reversible reagent can acylate both RNAs and proteins in high yields. Importantly, the groups can be removed with a water-soluble phosphine at room temperature in high yields, restoring the native undisturbed biomolecules. This project is innovative because it introduces an entirely new molecular strategy for fixation and stabilization of biomolecules. Both the molecules and methods described here are unknown in the literature. The work is significant because high-resolution molecular characterization and quantification of biomolecules is becoming a requirement for accurate analysis of disease and lesions. However, formalin fixation is universally recognized as a poor choice for preserving such samples. If successful, our approach will solve the problems of the complex and irreversible damage caused during and after formalin fixation. The new REAC method can be easily applied by non-chemists, and will yield the highest quality biomolecules in their native forms.